Abstract

Although obesity is a global epidemic, the physiological mechanisms involved are not well understood. Recent advances reveal that susceptibility to obesity can be programmed by maternal and neonatal nutrition. Specifically, a maternal low-protein diet during pregnancy causes decreased intrauterine growth, rapid postnatal catch-up growth and an increased risk for diet-induced obesity. Given that the synthesis of the neurotransmitter 5-hydroxytryptamine (5-HT) is nutritionally regulated and 5-HT is a trophic factor, we hypothesised that maternal diet influences fetal 5-HT exposure, which then influences development of the central appetite network and the subsequent efficacy of 5-HT to control energy balance in later life. Consistent with our hypothesis, pregnant rats fed a low-protein diet exhibited elevated serum levels of 5-HT, which was also evident in the placenta and fetal brains at embryonic day 16.5. This increase was associated with reduced levels of 5-HT$_{2C}$R, the primary 5-HT receptor influencing appetite, in the fetal, neonatal and adult hypothalamus. As expected, a reduction of 5-HT$_{2C}$R was associated with impaired sensitivity to 5-HT-mediated appetite suppression in adulthood. 5-HT primarily achieves effects on appetite by 5-HT$_{2C}$R stimulation of pro-opiomelanocortin (POMC) peptides within the arcuate nucleus of the hypothalamus (ARC). We show that 5-HT$_{2A}$Rs are also anatomically positioned to influence the activity of ARC POMC neurons and that mRNA encoding 5-HT$_{2A}$R is increased in the hypothalamus of in utero growth-restricted offspring that underwent rapid postnatal catch-up growth. Furthermore, these animals at 3 months of age are more sensitive to appetite suppression induced by 5-HT$_{2A}$R agonists. These findings not only reveal a 5-HT-mediated mechanism underlying the programming of susceptibility to obesity, but also provide a promising means to correct it, by treatment with a 5-HT$_{2A}$R agonist.

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Sponsorship

The research reported in this publication was supported by the Biotechnology and Biological Sciences Research Council (E007821/1 to M.S.M-G, R.L.C and E00797X/1; BB/K001418 /1 to L.K.H), the British Heart Foundation (FS/09/029/27902 to S.E.O.), the UK Medical Research Council Metabolic Diseases Unit (MC_UU_12012/4 to S.E.O and MC_UU_12012/1 to G.S.H.Y), the Wellcome Trust (WT081713 and WT098012 to L.K.H), the European Union (FP7-HEALTH-266408 Full4Health to G.S.H.Y) and the Helmholtz Alliance ICEMED to G.S.H.Y.

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